Camptothecin is an alkaloid isolated by Wall et al. [J. Am. Chem. Soc., 1966, 88, 3888-3890] for the first time from the tree Carmptotheca acumiiata, native to China and belonging to the Nyssaceae family.
The molecule consists of a pentacyclic structure with a lactone in ring E, which is essential for cytotoxicity.
For a review of the camptothecins and the problems relating to their use as medicaments as well as the solving of such problems, the reader is referred to EP 1 044 977, filed in the name of the present applicants.
The polyamines have for some time now been the subject of great interest in medicinal chemistry.
Putrescine, spermidine and spermine are the most intensively studied polyamines, in that they occur naturally in both prokaryotic and eukaryotic cells. Their role in cell physiology would appear to be multiple and, in certain respects, still unknown [J. Med. Chem., 2001, 44, 1-26]. At physiological pH these compounds are present as polycations, are capable of interacting with a substantial variety of cell constituents, such as RNA, DNA, nucleotides, proteins and other biological substances of an acid nature [J. Cell Biochem., 1991, 46, 37-47].
In oncology the polyamines are the subject of study for a number of reasons, namely, their polycationic nature at physiological pH, their influence on the ion channels of the cell membranes, and their interaction with various important transcriptional factors in human tumour forms [Biochemistry 1999, 38, 14765-74].
The conjugation of polyamines with cytotoxic drugs has also been described, for example with chlorambucil [Cancer Res., 1992, 52, 4190-5], where a substantial improvement in the therapeutic index has been observed, but also as a form of chemoprevention in combination with 3-indolylcarbinol [BMC-Cancer 2003, 3:2, 1471-2407].
Less frequent is the study of polyamine derivatives in protected form: for example, N-benzyl-derivatives [J. Med. Chem., 2001, 44, 3653-64].
The polyamines can be bound to cytotoxic molecules in order to influence their cell transport: for example, spermines have been conjugated with acridines [J. Med. Chem., 2002, 45, 5098-111] for the purposes of favouring a selective release of the latter at tumour cell level.
Polyamine residues have also been inserted in camptothecins (CPT) in position 7, such as iminomethyl derivatives [Bioorganic & Medicinal Chemistry Letters, 2001, 11, 291-4], and, in particular, the compound derived from spermine has been described in international patent application WO 0053607 filed in the name of the present applicant.